INTRODUCTION:

Ted Byers and Bud Loftus, two Food and Drug Administration (FDA) officials, first put out the idea of validation in the middle of the 1970s in an effort to enhance the quality of pharmaceuticals. A lot of elements need to be carefully considered in order to ensure the quality of the final product, such as the choice of high-quality components and materials, proper process and product design, process control, and in-process and final product testing¹.

Because medical items these days are so complex, regular end product testing is frequently insufficient to guarantee product quality for a number of reasons. Certain end-products tests exhibit restricted sensitivity. For example: Destructive testing may be necessary to demonstrate that the manufacturing process is sufficient in situations when end product testing is unable to prepare for all possible differences in the product that could affect its efficacy and safety.

Process validation is defined as the process of gathering and estimating data at various stages of pharmaceutical activities, beginning with the procedure design phase and continuing through production to establish the scientific indication that a procedure is effective in consistently producing high-quality results².

The process of obtaining documented confirmation that a product will be manufactured according to a particular procedure and that the product as a result will meet all of its pre-determined descriptions mentioned and quality characteristics is known as process validation, according to the USFDA³.

According to the FDA, systemic consideration of several crucial factors, such as the selection of high-quality raw materials and other components, the design of a suitable product and method, and the testing or standardization of procedures during in-process and final product testing, are what lead to the confirmation of product quality⁴.

Therefore, an increased level of confidence that each unique produced entity of a given batch or series of batches will meet the stipulated acceptable requirements can be established by means of a meticulous and optimal design as well as validation of the process and its control systems⁵.

According to WHO guidelines, validation is defined as a documented act that demonstrates or verifies that any part, substance, method, machine, system, or activity will, in general, lead to the anticipated results. Validation verifies that the procedure equipment can operate within the necessary parameters. Validations verify that procedures have been precisely defined, established, and are within expected control in addition to stating that the process has been enhanced^6-7.

Validation is the process of confirming that all GMPs have been adhered to successfully throughout the manufacturing process and that the anticipated outcomes will materialise. Evidence that is documented and guarantees that a pharmaceutical product may be manufactured with its encoded specifications and quality aspects intact by using an efficient method that is carried out within set parameters⁸.

Need of Pharmaceutical Validation:

Validation is a crucial component of quality assurance that entails a methodical examination of systems, facilities, and procedures to ascertain whether they fulfil their intended purposes sufficiently and consistently according to specifications. A technique that has been officially certified and proven to offer a high level of assurance that consistent batches will be generated that satisfy the necessary criteria is known as validated. While validation verifies that processes have been built correctly and are under control, it does not by itself improve processes⁹.

Scope of Validation:

Pharmaceutical validation covers a wide range of procedures connected to pharmaceutical manufacture, making it difficult to define the scope of validation. However, a systematic analysis of the pharmaceutical industry's actions will indicate, at the very least, the following areas that require pharmaceutical validation:¹⁰

· Analytical

· Instrument Calibration

· Process Utility services

· Raw materials

· Packaging materials

· Equipment

· Facilities

· Manufacturing operations

· Product Design

· Cleaning

· Operators

Importance of Validation:^11,12

· Quality Assurance

· Time-bound

· Process optimization

· Reduction of quality cost

· Nominal mix-ups, and bottle necks

· Minimal batch failures, improved efficiently and productivity

· Reduction in rejections

· Increased output

· Avoidance of capital expenditures

· Fewer complaints about process related failures

· Reduced testing in process and in finished goods

· More rapid and reliable start-up of new equipment’s

· Easier scale-up form development work

· Easier maintenance of equipment

· Improved employee awareness of processes

· More rapid automation

· Government regulation (Manufacturing approval and new product introduction are contingent upon compliance with validation standards)

VALIDATION PROTOCOL:¹³

In addition to being numbered, signed, and dated, the validation methodology should at the very least include the following details:

· Objective and Scope

· Responsibility

· Protocol Approval

· Validation Team

· Product Composition

· Process Flow Chart

· Manufacturing Process

· Review of Equipment’s/Utilities

· Review of Raw Materials and Packing Materials Review of Analytical and Batch Manufacturing Records

· Review of Batch Quantities for Validation (Raw Materials)

· Review of Batch Quantities for Validation (Packing Materials)

· HSE Requirements

· Review of Process Parameters Validation Procedure

· Sampling Location

· Documentation

· Acceptance Criteria

· Summary

· Conclusion

ADVANTAGES OF PROCESS VALIDATION:

· More extensive real-time process monitoring and modification.

· Improved capacity to assess product characteristics and process performance scientifically. For example, people, range, mean, and control limitations.

· Improved data and assessment capacities as well as heightened assurance about process repeatability and product excellence.

· Better ability to correlate validation results with target parameters and control limits for routine production.

· Enhanced reporting capability.

TYPES OF PROCESS VALIDATION^14-15

There are four main categories of validation processes, which are explained below:

1. Prospective Validation

2. Concurrent Validation

3. Retrospective Validation

4. Process Re-Validation

Prospective Validation:

carried out either before a new product is released into the market or before a product with major production process adjustments that could impact the product's attributes is released. It is a planned scientific approach that covers the first phases of formulation development, process development, specification setting, planning for in-process tests and sampling, batch record design, defining raw material specifications, pilot run completion, technology transfer from scale-up batches to commercial size batches, a list of major processes carried out, and environmental controls.¹⁶The validation technique is carried out in prospective validation before the process is used commercially. It is widely agreed upon that a proper validation of the process would consist of three successive batches/runs, within the final approved parameters, yielding a product of the desired quality. This confirms that there will be three commercial batches before marketing.¹⁵

Concurrent Validation:

A procedure where processing parameters are monitored using the present production batches. It provides information about the current batch under study and provides a limited level of confidence regarding the consistency of quality across batches.¹⁶In some situations, concurrent validation could be the most sensible course of action. These could occur when:¹⁵

· A previously approved process is being moved to a different location or to a contract manufacturer.

· Although the product has the same ratio of active to inactive substances, its strength differs from a previously approved product.

· Not enough lots were examined during the Retrospective Validation to provide a high level of assurance proving that the process is completely under control.

· The numbers of batches produced are limited.

· Process with low production volume per batch and market demand.

· The procedure used to manufacture medications that are in high demand because of a lack of availability.

· If the conditions listed below are met, concurrent validation is valid in all of the aforementioned scenarios.

· Pre-approved protocol for concurrent validation with rational.

· The head of the plant, the head process owner, or the head of the QMS must authorize every deviation request after it is made and justified.

· Product history and behaviour will be examined in light of test batches, scale-ups, and developmental phases.

· A comprehensive protocol needs to be designed to address the marketed product in the event that any unfavourable reactions are noticed throughout the concurrent validation process.

· Concurrent validation batches must be approved by all major disciplines and assembled into a report.

Retrospective Validation:

Done for a product that is currently on the market and is founded on copious amounts of data that have been gathered over time and across multiple batches. Retrospective validation is applicable to older items that need to be validated to meet the standards of division 2, Part C of the Regulation to be Food and Drugs Act, but were not validated by the fabricator when they were first marketed. Retrospective validation is only applicable for thoroughly established processes; it is inappropriate in cases where there have been recent modifications to the facilities, equipment, operating methods, or product composition. ^[16] The following are some crucial components of retrospective validation:¹⁵

· Batches produced for a specific amount of time (at least 10 batches in a row).

· Number of lots released per year.

· Batch size/strength/manufacturer/year/period.

· Master manufacturing/packaging documents.

· A list of manufacturing document modifications, process deviations, and remedial measures.

· Data for stability testing for several batches.

· Trend analysis, which includes concerns about quality.

Process Re-Validation:

Required if any of the formulation, main packaging components, raw material fabricator, significant equipment, or premises are altered, as well as any of the crucial process parameters. Process re-validation would also be necessary if batch performance fell short of both product and process requirements.¹⁶

· There are circumstances where re-validation is required. Some instances of planned or unforeseen modifications that can need re-validation are as follows:

· Modifications to the raw materials (physical characteristics that could impact the process or final product, such as moisture, viscosity, density, and particle size distribution).

· Modifications to the manufacturer's source of active raw materials.

· Changes in packaging material (primary container/closure system).

· Changes in the process (e.g., mixing time, drying temperatures and batch size).

· Changes in the equipment (e.g., addition of automatic detection system).

· Equipment replacements including a "like for like" exchange of equipment

Basic Concept of Process Validation:

Validation of the pharmaceutical process is the most significant and widely accepted cGMP parameter. The quality system (QS) rule makes process validation mandatory. Producing goods that are suitable for their intended usage on a regular basis is the aim of a quality system¹⁷.

In order to make sure that these objectives and principles are fulfilled, process validation is essential. Standardising the validation documents that need to be included with the submission file in order to receive marketing authorization is known as process validation. The goal of process validation, which is broadly applicable to manufacturing processes, is to help producers comprehend the requirements of the quality management system (QMS) with regard to process validation. The FDA states that systemic and careful attention to several critical variables, such as the selection of a quality process via in-process and end-product testing, is the foundation for assurance of product quality¹⁸.

The following could be said to be the fundamental validation principle:^19–20

Installation Qualification (IQ):

Proving by impartial proof that all essential components of the installation of the auxiliary systems and process equipment follow the manufacturer's certified specifications and that the equipment supplier's recommendations are appropriately taken into account.

The factors affecting IQ are:

· Features of equipment design (e.g., cleanability of construction materials, etc.)

· Installation circumstances (utility, functionality, wiring, etc.)

· Cleaning schedules, calibration, and preventative maintenance.

· Safety components.

· Prints, drawings, and manuals from suppliers.

· software documentation.

· List of spare parts.

· Environmental factors (including humidity, temperature, and clean room requirements).

Operational Qualification (OQ):

Establishing process control limits and action levels based on objective data that produce a product that satisfies all predefined requirements. OQ factors consist of:

· Process control limitations, such as those for setup conditions, line speed, temperature, pressure, and time.

· Parameters of the software.

· Raw material requirements.

· Operating procedures for processes.

· The requirements for handling materials.

· Change control procedures.

· Training.

· The process's short-term stability and capabilities (latitude studies or control charts).

· Worst-case scenarios, action levels, and probable failure modes.

· In order to optimise the procedure, statistically sound methods like screening experiments may be applied at this stage.

Performance Qualification (PQ):

Proving through objective data that the process regularly yields a product that satisfies all predefined standards when operating under expected circumstances. PQ factors consist of:

· Real product and process specifications and guidelines set forth in OQ.

· The product's acceptability.

· Guarantee of process capability according to OQ standards.

· Long-term stability and repeatability of the process.

Re-Qualification:

Equipment relocation or modification must be approved by the change control procedure after a thorough evaluation and authorization process. It is recommended that the equipment be requalified as part of this official examination. Modest alterations or those that don't directly affect the quality of the finished or in-process product should be managed using the preventive maintenance program's documentation system.

Validation Master Plan²¹

An overview of the complete validation process, including its planning, content, organisational structure, and content, should be included in the validation master plan. The planned timetable and the list/inventory of the items that need to be validated are its primary components. The validation master plan should contain all validation activities related to crucial technical operations that are pertinent to product and process controls within an organisation.

It should include revalidation as well as all prospective, contemporaneous, and retrospective validations. Since the Validation Master Plan is meant to be a summary, it must be simple, precise, and easy to understand. It should refer to already-published papers like policy documents, SOPs, validation methods, and reports rather than duplicating information that has already been documented elsewhere. Included in the format and content should be:

· Introduction: scope, location, schedule, and validation policy.

· Organizational structure: duties assigned to employees.

· Plant, process, or product description: justification for additions or deletions, as well as the scope of validation.

· Particular process factors that need special attention and are crucial.

· A matrix-formatted list of the systems, processes, and products that need to be validated, along with the validation methodology.

· Key acceptance criteria, real status, and revalidation operations.

· Format for documentation.

· Making use of the required SOPs.

· Schedules for every validation project and its subsidiary projects.

Documentation^22-23

It is necessary to create a documented protocol that details the qualifying and validation procedures. It is necessary to examine and approve the protocol. Acceptance criteria and crucial procedures should be outlined in the protocol. A report that summarises the findings, comments on any deviations noticed, and draws the necessary conclusions—including suggesting adjustments required to address inadequacies—should be created and cross-referenced with the qualification and/or validation process. Any modifications to the protocol-defined plan must be justified appropriately and documented. A format release for the subsequent qualification and validation phase should be made as a formal authorization following the completion of an acceptable qualification. Process qualification and ongoing process verification are the times when cGMP requires the most documentation, both in terms of quantity and type. Research conducted during these phases needs to follow cGMPs and have approval from the quality unit in line with the rules (21 CFR 211.22 and 211.100).

Validation Report^24-25

After the validation is finished, a documented report ought to be made available. It should be authorised and approved (signed and dated) if it is deemed suitable.

The following should be included in the report, at minimum:

· The study's title and goal.

· A reference to of protocol.

· Specifics of the content.

· Instruments.

· Cycles and programmesutilised.

· Specifics of protocols and testing techniques.

· Outcomes (weighed against acceptance standards).

· Suggestions regarding the upper limit and future application criteria.

CONCLUSION:

The term "validation" is most commonly used in medication research, manufacturing, and product specification. The consistency and reliability of a validated process in producing a quality product is critical for an industry. Validation is the process of ensuring the identity, strength, purity, safety, and efficacy of a pharmaceutical product. Pharmaceutical process validation is one of the most significant and widely recognized cGMP factors. The product should be constructed robustly enough to survive fluctuations in the manufacturing process, and the manufacturing process should be capable and stable to ensure continuing safe and acceptable product performance. Process validation is a sequence of activities that occur throughout the product and process's lifecycle.

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Received on 24.02.2024 Modified on 21.05.2024

Asian J. Pharm. Tech. 2024; 14(3):251-256.

DOI: 10.52711/2231-5713.2024.00041